Cyclic Progestin Regimens and Kits

ABSTRACT

A method of contraception is provided which involves delivery of 21 to 27 consecutive days of a progestin in the absence of an estrogen or other steroidal compound, followed by 1 to 7 days without an effective amount of an active agent. Also described is a pharmaceutically useful kit to facilitate delivery of this regimen.

BACKGROUND OF THE INVENTION

Soon after the introduction of progestin/estrogen combination oralcontraceptives (OCs) pills in 1960, several progestin-only pills (POPs)were introduced. The dose of the progestin in the POPs was made lowerthan in the combined OCs to minimize the occurrence of amenorrhearesulting from complete ovarian suppression. Consequently, ovulation wasinhibited in about half the users of POPs. (The standard POPs primarilydepend upon cervical mucus thickening to provide contraceptiveprotection for those who ovulate). Partly because of the lower progestindose, the absence of exogenous estrogen and the absence of regularwithdrawal bleed, POP users have a much higher rate of unscheduledbreakthrough bleeding and spotting than combination OC users. Primarilybecause of the bleeding problems, POPs are used by only about 1-2% ofcontracepting women, compared to about 30% using combination OCs.

What is needed is a progestin-containing contraceptive which avoidsbreakthrough bleeding and spotting problems.

SUMMARY OF THE INVENTION

The present invention provides a contraceptive regimen which involvesdelivery of an effective amount of a progestin for 21 to 27 consecutivedays followed by 1 to 7 consecutive days without delivery of same. Inone embodiment, the progestin is5-(4,4-Dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile,also termed tanaproget.

The invention further provides a pharmaceutical kit for use in deliveryof the regimen.

Other aspects of the invention will be readily apparent from thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a method of contraceptionin a female of child-bearing age. In this method, a progestin, orcombination of progestins, is delivered for a period of consecutive daysas the sole active (i.e., anti-contraceptive) agent in order to preventconception.

In another aspect, the present invention provides for the use of aprogestin, or combination of progestins, in preparing a medicamentuseful for contraception in a female of child-bearing age. In oneembodiment, the medicament comprises one phase in which, from 21 to 27daily dosage units are consecutively administered, each containing anactive agent comprising a progestin. In a further embodiment, themedicament also comprises from 1 to 7 daily dosage units of apharmaceutically acceptable placebo for administration in a secondphase. In other embodiments, progestins are useful in preparingmedicaments useful in any of the methods of contraception describedherein.

Without wishing to be bound by theory, it is believed that thisinvention will reduce the bleeding problems of conventionalprogestin-only contraceptives in two ways. First, due to theincorporation of 1 to 7 days in each cycle with no effective amount of aprogestin, a regular withdrawal bleed will occur approximately every 28days. Second, increasing the progestin dose above standardprogestin-only contraceptives produces almost complete ovulationinhibition and the composition of the invention does not depend oncervical mucus thickening to maintain the contraceptive effectiveness asdo conventional progestin-only regimens.

The term “progestin,” as used herein, refers to any progestationallyactive compound, i.e., any compound that binds to and activates theprogesterone receptor. Representative progestins include progesteronesynthetic derivatives such as, for example, 17-hydroxy progesteroneesters, 19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosteroneand derivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, dl-norgestrel,d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel, etonorgestrel, norgestimate andnorelgestromin. Other compounds with progestational activity used inoral contraceptives include chlormadione, dienogest, and drospirenone.

In one embodiment, the progestin is5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile,also termed tanaproget and NSP-989. This compound can have the formula:

and encompasses pharmaceutically acceptable salts, esters or otherprodrug forms thereof. This compound and methods of making same aredescribed in U.S. Pat. No. 6,436,929, U.S. patent application Ser. No.11/113,794 (filed Apr. 25, 2005), and U.S. Provisional PatentApplication Nos. 60/675,550 (filed Apr. 28, 2005); 60/675,551 (filedApr. 28, 2005); 60/675,559 (filed Apr. 28, 2005); 60/675,737 (filed Apr.28, 2005); and 60/675,738 (filed Apr. 28, 2005).

In addition, other progestins described in U.S. Pat. Nos. 6,436,929;6,355,648; 6,521,657; 6,407,101; 6,562,857; and 6,358,947, US PatentPublication No. 2003-0158182, and U.S. Provisional Patent ApplicationNo. 60/601,254 (filed Aug. 13, 2004) may be useful in the methods andkits of the invention.

The progestin compounds useful in the present invention can be used inthe form of salts derived from pharmaceutically or physiologicallyacceptable acids or bases. These salts include, but are not limited to,the following salts with inorganic acids such as hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid and, as the case may be,such organic acids as acetic acid, oxalic acid, succinic acid, andmaleic acid. Other salts include salts with alkali metals or alkalineearth metals, such as sodium, potassium, calcium or magnesium in theform of esters, carbamates and other conventional “pro-drug” forms,which, when administered in such form, convert to the active moiety invivo.

The method of the invention is performed for a period of timecorresponding to the length of a menstrual cycle, i.e., in the range of23 to 35 days, with 28 days being the average. Thus, the method of theinvention involves delivering a daily dosage unit containing aneffective amount of an active agent consisting of a progestin to afemale of child bearing age over a period of 18 to 28 consecutive daysfollowed by 1 to 7 consecutive days in which no effective amount of anactive agent is delivered to the subject.

The term “effective amount” of a progestin(s) is a dosage that providescontraception. Without being bound by theory, this is achieved primarilyby preventing ovulation. The term “no effective amount” of aprogestin(s) is used to refer to the 1 to 7 days following delivery ofan effective amount of the progestin(s). During this period, preferably,no amount of a progestin(s) is delivered to the animal. However, it ispossible, that a sustained release formulation or other delivery methodmay be “leaky” and continue to deliver low amounts of a progestin whichare not effective at contraception during this period. The phrase “noeffective amount” encompasses delivery of no amount of progestin(s).

According to the present invention, a female is preferably a human.However, as used herein, a female can include non-human mammals, e.g.,cattle or livestock, horses, pigs, domestic animals, etc.

In one aspect, the method of invention involves delivering a dailydosage unit containing an active agent consecutively for at least 21 of28 consecutive days. In the embodiment, the regimen consists ofdelivering a progestin to a female of child bearing age over a period of21 to 27 consecutive days followed by 1 to 7 consecutive days in whichno effective amount or no amount of active agent is delivered to thesubject. Optionally, the period of 1 to 7 days in which no effectiveamount of an active agent is delivered to the subject can involvedelivery of a second phase of daily dosage units of 1 to 7 days of apharmaceutically acceptable placebo. Alternatively, during this “placeboperiod”, no placebo is administered.

In one embodiment, the method of the invention involves delivering aprogestin as the sole active agent for 21 consecutive days followed by 7days in which no effective amount of an active agent is delivered.Optionally, during these 7 days, a second phase of 7 daily dosage unitsof an orally and pharmaceutically acceptable placebo can be delivered.

In another embodiment, the method of the invention involves delivering aprogestin as the sole active agent for 23 consecutive days followed by 5days in which no effective amount of an active agent is delivered.Optionally, during these 5 days, a second phase of 5 daily dosage unitsof an orally and pharmaceutically acceptable placebo can be delivered.

In still another embodiment, the method of the invention involvesdelivering a progestin as the sole active agent for 25 consecutive daysfollowed by 3 days in which no effective amount of an active agent isdelivered. Optionally, during these 3 days, a second phase of 3 dailydosage units of an orally and pharmaceutically acceptable placebo can bedelivered.

In still another embodiment, the method of the invention involvesdelivering a progestin as the sole active agent for 27 consecutive daysfollowed by 1 day in which no effective amount of an active agent isdelivered. Optionally, a second phase of 1 daily dosage unit of anorally and pharmaceutically acceptable placebo can be delivered.

This invention includes the use of pharmaceutical compositionscontaining one or more progestin compound(s) as the sole activeingredient in the formulation and regimen. The progestin compounds areformulated with a pharmaceutically acceptable carrier or excipient.

Suitably, the progestins used in the invention are formulated fordelivery by any suitable route including, e.g., transdermal, mucosal(intranasal, buccal, vaginal), oral, parenteral, etc, by any suitabledelivery device including, e.g., transdermal patches, topical creams orgels, a vaginal ring, among others. In a further embodiment, theprogestins are delivered by any suitable route in a sustained releaseformulation. Such sustained release formulations are known to those ofskill in the art.

When the compounds are employed for the above utilities, they may becombined with one or more pharmaceutically acceptable carriers orexcipients, for example, solvents, diluents and the like. Whenformulated for oral delivery, the progestin compound can be in the formof a tablet, capsule, caplet, gel tab, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like. When formulated for parenteral delivery, the compositions canbe delivered in the form of sterile injectable solutions or suspensionscontaining from about 0.05 to 5% suspending agent in an isotonic medium.Such pharmaceutical preparations may contain, for example, from about 25to about 90% of the active ingredient in combination with the carrier,more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and thedegree of ovarian suppression desired. However, in general, satisfactoryresults are obtained when the compounds of the invention areadministered at a daily dosage of from about 0.03 to 0.6 mg, or about0.1 to about 0.5 mg, preferably given daily or in a sustained releaseform. This dosage regimen may be adjusted to provide the optimaltherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation.

These active compounds (one or more progestins) may be administeredorally. Solid carriers include starch, lactose, dicalcium phosphate,microcrystalline cellulose, sucrose and kaolin, while liquid carriersinclude sterile water, non-ionic surfactants, ethanol (e.g., glycerol,propylene glycol and liquid polyethylene glycols), suitable mixturesthereof, and vegetable or edible oils such as corn, peanut and sesameoils, as are appropriate to the nature of the active ingredient and theparticular form of administration desired. Adjuvants customarilyemployed in the preparation of pharmaceutical compositions may beadvantageously included, such as flavoring agents, coloring agents,preserving agents, and antioxidants, for example, vitamin E, ascorbicacid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered via a vaginal ring.Suitably, use of the vaginal ring is timed to the 28 day cycle. In oneembodiment, the ring is inserted into the vagina, and it remains inplace for 3 weeks. During the fourth week, the vaginal ring is removedand menses occurs. The following week a new ring is inserted to be wornanother 3 weeks until it is time for the next period. In anotherembodiment, the vaginal ring is inserted weekly, and is replaced forthree consecutive weeks. Then, following one week without the ring, anew ring is inserted to begin a new regimen. In yet another embodiment,the vaginal ring is inserted for longer or shorter periods of time.

For use in the vaginal ring, a progestin compound is formulated in amanner similar to that described for contraceptive compounds previouslydescribed for delivery via a vaginal ring. See, e.g., U.S. Pat. Nos.5,972,372; 6,126,958; and 6,125,850.

Optionally, a progestin composition can be formulated for parenteraldelivery in a sustained release formulation and administered byinjection, e.g., monthly or quarterly.

In another aspect of the invention, a progestin compound is formulatedfor delivery via a cream or a gel, by a suitable route. Suitably,carriers for such routes are known to those of skill in the art.

In still another aspect of the invention, the progestin compound(s) aredelivered via a transdermal patch. Suitably, use of the patch is timedto the 28 day cycle. In one embodiment, the patch is applied via asuitable adhesive on the skin, where it remains in place for 1 week andis replaced weekly for a total period of three weeks. During the fourthweek, no patch is applied and menses occurs. The following week a newpatch is applied to be worn to begin a new regimen. In yet anotherembodiment, the patch remains in place for longer, or shorter periods oftime.

This invention also includes kits or packages of pharmaceuticalformulations designed for use in the regimens described herein.Suitably, the kits contain one or more progestin compounds as describedherein. In one embodiment, the progestin is selected from among17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters,17α-ethinyltestosterone and derivatives thereof,17α-ethinyl-19-nor-testosterone and derivatives thereof, norethindrone,norethindrone acetate, ethynodiol diacetate, dydrogesterone,medroxy-progesterone acetate, norethynodrel, allylestrenol,lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone,dimethiderome, ethisterone, cyproterone acetate, levonorgestrel,dl-norgestrel, d-17α-acetoxy-13β-ethyl-17α-a-ethinyl-gon-4-en-3-oneoxime, cyproterone acetate, gestodene, desogestrel, etonorgestrel,norgestimate, norelgestromin, chlormadione, dienogest, and drospirenone.In addition, other progestins described in U.S. Pat. Nos. 6,436,929;6,355,648; 6,521,657; 6,407,101; and 6,562,857, may be useful in themethods and kits of the invention.

In one desirable embodiment, the progestin is NSP-989, also termedtanaproget, or a pharmaceutically acceptable salt or prodrug thereof.

Advantageously, for use in the kits of the invention, the progestin isformulated for the desired delivery vehicle and route. For example, aprogestin can be formulated for oral delivery, parenteral delivery,vaginal ring, transdermal delivery, or mucosal delivery.

In one embodiment, the kit of the invention is designed for daily oraladministration over a 28-day cycle, preferably for one oraladministration per day, and organized so as to indicate a single oralformulation or combination of oral formulations to be taken on each dayof the 28-day cycle. Preferably each kit will include oral tablets to betaken on each the days specified; preferably one oral tablet willcontain each of the combined daily dosages indicated. For example, a kitof the invention can contain 21 to 27 daily dosage units of an effectiveamount of an active agent and, optionally, 1 to 7 daily dosage units ofa placebo and other appropriate components including, e.g., instructionsfor use.

The kit of the invention is preferably a pack (e.g., a blister pack)containing daily doses arranged in the order in which they are to betaken.

In another embodiment, the kit of the invention is designed for weeklyor monthly administration via a vaginal ring over a 28-day cycle.Suitably, such a kit contains individual packaging for each of thevaginal rings, i.e., one to three, required for a monthly cycle andother appropriate components, including, e.g., instructions for use.

In another embodiment, the kit of the invention is designed for weeklyor monthly administration via a transdermal patch over a 28-day cycle.Suitably, such a kit contains individual packaging for each of thepatches, i.e., one to three, required for a monthly cycle and otherappropriate components including, e.g., instructions for use.

In still another embodiment, the kit of the invention is designed forparenteral delivery of the progestin. Such a kit is typically designedfor delivery at home and may include needles, syringes, and otherappropriate packaging and instructions for use.

In yet another embodiment, the kit of the invention contains a progestincompound in a gel or cream formulation. Optionally, the kit can includeappropriate packaging such as a tube or other container, an applicator,and/or instructions for use.

In each of the regimens and kits described herein, it is preferred thatthe daily dosage of each pharmaceutically active component of theregimen remain fixed in each particular phase in which it isadministered. It is also understood that the daily dose units describedare to be administered in the order described, with the first phasefollowed in order by the optional second phase. To help facilitatecompliance with each regimen, it is also preferred that the kits containthe placebo described for the final days of the cycle. It is furtherpreferred that each package or kit comprise a pharmaceuticallyacceptable package having indicators for each day of the 28-day cycle,such as a labeled blister package, dial dispenser, or other packagesknown in the art.

These dosage regimens may be adjusted to provide the optimalcontraceptive effect. For example, several divided doses of eachcomponent may be administered daily or the dose may be proportionallyincreased or reduced as indicated by the contraceptive effectiveness. Inthe descriptions herein, reference to a daily dosage unit may alsoinclude divided units which are administered over the course of each dayof the cycle contemplated.

The following examples are illustrative only and are not intended to bea limitation on the present invention.

EXAMPLE 1 Ovulation Inhibition by the Progestin Compound NSP-989

The activity of NSP-989 was evaluated orally in three 3 different ratmodels for progestin activity along with reference progestinsmedroxyprogesterone acetate (MPA) and trimegestone (TMG) in 2% Tween80/0.5% methylcellulose vehicle. These models are described in Parts A,B and C of this example.

Effect of NSP-989 in the Rat Ovulation Inhibition Model

The ovulation inhibition assay measures a compound's ability to inhibitovulation in adult female rats. This activity is essential forcontraceptive efficacy. In this assay, NSP-989 had a mean ED₁₀₀ value of0.03 mg/kg, whereas both TMG and MPA had ED₁₀₀ values of 1 mg/kg (n=2-to 3).

Random cycling mature female Sprague-Dawley rats (˜200 g) were obtainedfrom Charles River Laboratory (Boston, Mass.). Rats were synchronizedfor estrus with 2 μg of LHRH (in phosphate buffered saline containing0.1% bovine serum albumin) administered subcutaneously (sc) per rat at0900 h and again at 1600 h. Animals were allowed to rest for 8 daysbefore the administration of test compounds. Animals were then grouped,with 7 to 9 rats per treatment group. The morning of the ninth dayfollowing LHRH treatment, the rats were treated with test compounds oncedaily, by gavage. This continued for 4 consecutive days. The animalswere euthanized the morning following the last treatment. Oviducts wereremoved, placed between 2 glass slides, and viewed through a dissectingmicroscope to count ova. The number of animals presenting ova in theoviduct from each treatment group and the number of ova in the oviductof each animal were recorded.

B. Rat Decidualization Model

The second rat model to determine progestational activity is the uterinedecidualization assay in adult ovariectomized rats. Only compounds thatare progesterone receptor agonists will be active in this model, as aprogestin is absolutely required to transform uterine stromal cells todifferentiated decidual cells.

Rat decidualization assay was run as described previously [Lundeen S G,et al., “Rat uterine complement C3 expression as a model forprogesterone receptor modulators: characterization of the new progestintrimegestone”, J Steroid Biol Mol Biol. 2001; 78:137-143.]

Briefly, mature female Sprague-Dawley rats (˜220 g) were ovariectomizedat least 10 days prior to treatment to reduce circulating sex steroids.NSP-989 was administered once daily for seven 7 days orally by gavage(0.5 ml) in 2% Tween 80/0.5% methyl-cellulose vehicle. Approximately 24hours after the third daily treatment, decidualization was induced inone uterine horn of each anesthetized rat by scratching theantimesometrial luminal epithelium with a blunt 21-gauge needle. Thecontralateral horn was not scratched and served as a non-stimulatedcontrol. Animals were euthanized by CO₂ asphyxiation 24 hours followingthe final treatment. The uteri were removed, and trimmed of fat, and thedecidualized (D) and control (C) horns were weighed separately. Thedecidual response is expressed as D/C.

NSP-989 induced endometrial decidualization with an ED₅₀ value of 0.01mg/kg (n=23) and was approximately 40- and 100-fold more potent than MPAand TMG, respectively (Table 1).

TABLE 1 Summary of Progestational Activity of NSP-989 in Various RodentModels Rabbit Rat Ovulation Rat Decidual Clauberg Inhibition Assay AssayRat C3 Assay Assay ED₁₀₀ ED₅₀ ED₅₀ AED₅₀ Compound (mg/kg, po) (mg/kg,po) (mg/kg, po) (mg/kg, po) NSP-989 0.03 0.01 0.0005 0.001 MPA 1.0 0.40.03 0.03 TMG 1.0 1.0 0.005 0.001

C. Rat Uterine C3 Model

The third model for PR agonist activity was the adult ovariectomized ratuterine C3 model. This assay evaluates the ability of a progestin toblock estrogen-induced C3 expression in the uterine epithelium.

Ovariectomized female, 60 day-old Sprague-Dawley rats were obtained fromHarlan (Indianapolis, Ind.). Ovariectomies were performed by thesupplier a minimum of 8 days prior to before treatment. The rats wererandomized and placed in groups of 6. The animals were treated oncedaily for (2) two days orally by gavage (p.o.) in a volume of 0.5 mL. Onthe second day of treatment, the animals were also treated with EE (0.08mg/kg body weight (BW)) orally by gavage. Approximately 24 hours afterthe final treatment, the animals were euthanized by CO₂ asphyxiation.The uteri were then removed, stripped of remaining fat and mesentery,weighed, and snap-frozen on dry ice. Total RNA was isolated from theuteri using the Trizol Reagent (GibcoBRL) as described by themanufacturer. Real-time reverse transcription polymerase chain reaction(RT-PCR) as previously reported [Sampath D, et al., “Aberrant expressionof Cyr61, a member of the CCN (CTGF/Cyr61/Cef10/NOVH) family, anddysregulation by 17b-estradiol and basic fibroblast growth factor inhuman uterine leiomyomas” J Clin Endocrinol Metab 2001; 86:1707-1715]was used to quantitate complement C3 expression. Briefly, RNA sampleswere DNAse-I treated using a DNA-free kit (Ambion). A total of 50 ng ofRNA was analyzed in triplicate using C3 specific primer pair (5′primerGGTCGGTCAAGGTCTACTCCTACTA [SEQ ID NO: 1], 3′primer CACAGCGGCACATTTCATTG[SEQ ID NO: 2]) and customized probe(6FAM-AGCATTCCATCGTCCTTCTCCGGATG-TAMRA [SEQ ID NO: 3]). C3 messenger RNA(mRNA) levels were normalized to 18s 18S ribosomal RNA contained withineach sample reaction using primers and probe supplied by PE AppliedBiosystems.

The mean ED₅₀ value for NSP-989 was 0.0005 mg/kg (n=6). Both MPA and TMGhad mean ED₅₀ values of 0.03 and 0.005 mg/kg, respectively in thisassay. In summary, in the rats, in several unrelated models forprogestin activity, NSP-989 was 3010- to 10060-fold more potent than thereference progestins used in these studies.

D. Rabbit Endometrial Transformation (Clauberg) Assay

In addition to the rat progestational models described above, NSP-989was also evaluated in the Clauberg model, a classic progestational assayin the rabbit endometrial transformation model [McPhail M K, “The assayof progestin.” J Physiol 1934; 83:145-1567]. Briefly, immature femaleNew Zealand White rabbits (˜1 kg body weight) were injectedsubcutaneously with 5 μg 17β-estradiol (E₂)/rabbit/day for sixconsecutive days. Beginning 24 hours after the final E₂ injection,vehicle alone or test compounds were given orally for (5) fiveconsecutive days. Progestational activity was determined by increases inuterine weight and endometrial glandular arborization (McPhail Index).

In limited dose response studies, NSP-989 had an estimated ED₅₀ (AED₅₀)of 0.001 mg/kg. Its potency in this assay was similar to TMG and about30-fold more potent than MPA.

EXAMPLE 2 Cyclic Regimen Using Progestin Compound

A phase 2, randomized, double-blind, multicenter, dose-ranging study of3 doses of NSP-989 in a 21-day regimen followed by 7 days of placebopills, and a comparator (the combination steroidal OC desogestrel (DSG)150 μg/20 μg ethinyl estradiol for 21 days followed by 2 days of placebopills, followed by 5 days of 10 μg EE, marketed in the United Statesunder the name Mircette) is planned.

Approximately 20 sites will participate with approximately 16 subjectsper site. However, the enrollment will be competitive, and additionalsubjects can be enrolled at any site.

The study will have 2 parts. Part 1 (days 1-84) of the study willevaluate the ability of NSP-989 to produce ovarian suppression, alongwith evaluating cycle control, side effects, and metabolic data. Part 2(days 85-168) will continue to follow the subjects to collect cyclecontrol, side effects, and metabolic data. The study will be monitoredroutinely by the blinded project medical monitor and study team forefficacy failures and safety. Each subject will participate for up to 9months, depending on the length of the subject's screening period. Eight(8) cycles will be observed. The first cycle will be a baselineobservation of ovulation. Six (6) treatment cycles will be followed by 1posttreatment observation cycle to assess return to ovulation. Thesubjects will be healthy women of ≧18 years of age who are younger than36 years at the time of randomization. Subjects must have hadspontaneous regular (24- to 32-day) menstrual cycles for the 3-monthperiod preceding entry into the pretreatment observation cycle,excluding postabortal and nonbreastfeeding postpartum subjects.Postabortal and nonbreastfeeding postpartum subjects must have completedat least 1 regular (24- to 32-day) spontaneous menstrual cycle beforeentry into the pretreatment observation cycle. The pretreatmentobservation cycle for all subjects will begin on day 1 of the subsequentspontaneous menses after completion of the prestudy screening (visit 1).

The pretreatment observation cycle is a control cycle; no test articlewill be administered. Each subject will begin test article on the firstday of her menstrual bleeding (first subject pack only). Each subjectpack will contain NSP-989 or the steroid combination OC comparator.Subjects will take NSP-989 orally, once daily for 21 days (days 1through 21), followed by 7 days of placebo pills (days 22 through 28)for 6 cycles. Subjects assigned to a steroid combination OC comparator,DSG 150 μg, will take test article orally, once daily for 21 days (days1 through 21), followed by 2 days of placebo pills (days 22 through 23),followed by 5 days of 10 μg EE (days 24 through 28) for 6 cycles. Therewill also be a posttreatment cycle in which no test article will beadministered and return to ovulation will be assessed.

Each subject will be randomly assigned to receive one of the following:

Group Treatment A 100 μg of NSP-989 for 21 days followed by 7 days ofplacebo pills B 200 μg of NSP-989 for 21 days followed by 7 days ofplacebo pills C 300 μg of NSP-989 for 21 days followed by 7 days ofplacebo pills D Desogestrel 150 μg for 21 days followed by 2 days ofplacebo pills, followed by 5 days of 10 μg EE

Each subject will begin test article on the first day of her menstrualbleeding (first subject pack only). Subjects will take test articleorally, once daily for 28 days, at approximately the same time each day.All subsequent subject packs will begin following day 28 of the previouspill pack. Subjects will take test article daily without interruptionduring the treatment cycles.

It is anticipated that one or more treatment groups A, B and C receivinga regimen of the invention will have experience effective contraception,cessation of ovulation, and all groups will have a withdrawal bleedduring the fourth week of each month of treatment.

EXAMPLE 3

A blister pack with 28 blister containers is made with a cardboard,paperboard, foil or plastic backing and enclosed in a suitable cover.The blister containers are arranged to house a sequence of 21 pills eachproviding a daily dose of 100 μg of NSP-989 followed by 7 daily doses ofplacebo pills (or 7 empty blisters). Each blister container mayconveniently be numbered or otherwise marked, e.g., starting with thefirst of the 21 dosage units that contain the active ingredient followedby 7 empty blisters or by 7 dosage units that contain no active agent.

All patents, patent publications, other publications listed in thisspecification, and priority U.S. patent application Ser. No. 12/772,280,filed May 3, 2010; U.S. patent application Ser. No. 11/174,592, filedJul. 6, 2005; and U.S. Provisional Patent Application No. 60/586,045,filed Jul. 7, 2004; and the sequence listing, are incorporated herein byreference. While the invention has been described with reference toparticular embodiments, it will be appreciated that modifications can bemade without departing from the spirit of the invention. Suchmodifications are intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A pharmaceutically useful kit adapted for dailyoral administration, which comprises: (a) 21 to 27 daily dosage units ofan effective amount of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and (b) one or more packages for said daily dosage units.
 2. Thepharmaceutically useful kit according to claim 1, further comprising:(c) 1 to 7 daily dosage units of an orally and pharmaceuticallyacceptable placebo.
 3. The pharmaceutically useful kit according toclaim 2, which comprises: (a) 21 daily dosage units of said5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and (c) 7 daily dosage units of said orally placebo.
 4. Thepharmaceutically useful kit according to claim 2, which comprises: (a)23 daily dosage units of said5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and (c) 5 daily dosage units of said placebo.
 5. The pharmaceuticallyuseful kit according to claim 2, which comprises: (a) 25 daily dosageunits of said5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and (c) 3 daily dosage units of said placebo.
 6. The pharmaceuticallyuseful kit according to claim 2, which comprises: a) 27 daily dosageunits of said5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and b) 1 daily dosage unit of said placebo.
 7. The pharmaceuticallyuseful kit according to claim 1, wherein said daily dosage units aretablets.
 8. The pharmaceutically useful kit according to claim 1,wherein said daily dosage units are a topical cream or gel.
 9. Thepharmaceutically useful kit according to claim 2, wherein said placebolacks an effective amount of said progestin.
 10. The pharmaceuticallyuseful kit according to claim 1, which lacks a second steroidalcompound.
 11. The pharmaceutically useful kit according to claim 1,wherein said second steroidal compound is an estrogen.
 12. Thepharmaceutically useful kit according to claim 1, wherein said effectiveamount is about 0.03 to about 0.6 mg.
 13. The pharmaceutically usefulkit according to claim 12, wherein said effective amount is about 0.1 toabout 0.5 mg.
 14. The pharmaceutically useful kit according to claim 13,wherein said effective amount is about 0.1.
 15. The pharmaceuticallyuseful kit according to claim 13, wherein said effective amount is about0.2 mg.
 16. The pharmaceutically useful kit according to claim 13,wherein said effective amount is about 0.3 mg.
 17. A pharmaceuticallyuseful kit adapted for daily oral administration, consisting essentiallyof: (a) 21 to 27 daily dosage units of an effective amount of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and (b) one or more packages for said daily dosage units.
 18. Thepharmaceutically useful kit according to claim 17, which lacks a secondsteroidal compound.
 19. A pharmaceutically useful kit adapted for dailyoral administration, consisting of: (a) 21 to 27 daily dosage units ofan effective amount of5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile;and (b) one or more packages for said daily dosage units.